TY - JOUR
T1 - Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43
AU - Maroto, Irene B.
AU - Costas-Insua, Carlos
AU - Berthoux, Coralie
AU - Moreno, Estefanía
AU - Ruiz-Calvo, Andrea
AU - Montero-Fernández, Carlos
AU - Macías-Camero, Andrea
AU - Martín, Ricardo
AU - García-Font, Nuria
AU - Sánchez-Prieto, José
AU - Marsicano, Giovanni
AU - Bellocchio, Luigi
AU - Canela, Enric I.
AU - Casadó, Vicent
AU - Galve-Roperh, Ismael
AU - Núñez, Ángel
AU - Fernández de Sevilla, David
AU - Rodríguez-Crespo, Ignacio
AU - Castillo, Pablo E.
AU - Guzmán, Manuel
N1 - Funding Information:
This work was supported by the Spanish Ministerio de Ciencia e Innovación (MICINN/FEDER; grants RTI2018-095311-B-I00 and PID2021-125118OB-I00 to M.G., SAF-2017-87629-R to E.I.C. and V.C., PID2020-113938RB-I00 to E.M. and V.C., BFU 2017-83292-R to J.S.-P., and PID2020-119358GB-I00 to D.F.d.S.) and the NIH (grants R01 MH116673, R01 MH125772, R01 NS115543, and R01 NS113600 to P.E.C.). L.B. and G.M. were supported by INSERM. I.B.M. and C.C.-I. were supported by contracts from the Spanish Ministerio de Universidades (Formación de Profesorado Universitario Program, references FPU15/01833 and FPU16/02593, respectively). We are indebted to Rodrigo Barderas-Machado, Alba Hermoso-López, and Lucía Rivera-Endrinal for expert technical assistance.
Funding Information:
This work was supported by the Spanish Ministerio de Ciencia e Innovación (MICINN/FEDER; grants RTI2018-095311-B-I00 and PID2021-125118OB-I00 to M.G., SAF-2017-87629-R to E.I.C. and V.C., PID2020-113938RB-I00 to E.M. and V.C., BFU 2017-83292-R to J.S.-P., and PID2020-119358GB-I00 to D.F.d.S.) and the NIH (grants R01 MH116673, R01 MH125772, R01 NS115543, and R01 NS113600 to P.E.C.). L.B. and G.M. were supported by INSERM. I.B.M. and C.C.-I. were supported by contracts from the Spanish Ministerio de Universidades (Formación de Profesorado Universitario Program, references FPU15/01833 and FPU16/02593, respectively). We are indebted to Rodrigo Barderas-Machado, Alba Hermoso-López, and Lucía Rivera-Endrinal for expert technical assistance.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function.
AB - The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function.
UR - http://www.scopus.com/inward/record.url?scp=85153538725&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85153538725&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-38026-2
DO - 10.1038/s41467-023-38026-2
M3 - Article
C2 - 37085487
AN - SCOPUS:85153538725
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2303
ER -